19-hydroxypregnene-3, 11, 20-triones, derivatives and intermediate 1, 19-isopropylidenedioxy steroids used in their preparation



Un t ds are s 19 HYDROXYPREGNENE 3,11,20 TRIONES, DE- RIVATIVES AND INTERMEDIATE 1,19-ISOPRO- PYLIDENEDIOXY STEROIDS USED IN THEIR PREPARATION John S. Baran, Chicago, Ill., assignor'to G. Searie & Co., Chicago, Ill., a corporation of Delaware No Drawing. Filed Sept. 28, 1959, Ser. No. 842,566 Claims. *(Cl. 260-23955) The present invention relates to 11,19-isopropylidenedioxy steroids and to their 19-hydroxy-pregnene-3,11,20- trione derivatives.. 'The 1,19-isopropylidenedioxy derivatives of this invention can be represented by the general structural formula a IRCOO In this formula A can represent a -COCH --COCH l, COCH OH radical. The radical R can represent such lower alkyl radicals as methyl, ethyl, straight chain or branched propyl, butyl, amyl, or hexyl.

The compounds of the foregoing structural formula are conveniently prepared using as a starting material ouabagenin 1,19-acetonide (M annich and Siewert, Berichte 75: 737; 1942). This compound is first acylated in the 3- and ll-positions'by treatment with an alkanoic acid anhydride of thestructural formula (RCO) O and the resulting diacylate is then selectively dehydrated at carbon-14 with thionyl chloride in pyridine to yield the 3,1 1-diacyl-l4-anhydroouabagcnin 1,19-acetonide which is hydrogenated by use of a palladium catalyst to yield 3,11 diacyl-14-desoxyouabagenin 1,19 acetonide. This product is treated with ozone, then with zinc and "acetic acid, and subsequently with aqueous alkaline alkanol to yield the 3fa,lla-diacyloxy 1555,1911 tetrahydroxy pregnan-ZO-one 1,19-acetonide (3,9,11u-diacyloxy-lfl,19- isopropylidenedioxy-S [9,21 dihydroxypregnan 20 one) The 2l-hydroxy group is then selectively esterfied, typically with p-toluene s ulfonyl chloride in pyridine or an analogous base and the resulting ester is treated with sodium iodide to yield the compound of the foregoing structural formula wherein A is a CH I group. Reduction with zinc, typically in acetic acid, removes the iodine and yields the 313,11a-diacyloxy-1fi,5fi,19-trihydroxypregnan-ZO-one 1,19-acetonide. This 3,11-diester can be deesterified by treatment with aqueous alkaline 'alkanol and the resulting 1fi,3fl,5;9,11a,19-pentahydroxypregnan- 2 0-one 1,19-acetonide oxidized with chromic acid and pyridine to yield 15,55,19-trihydroxypregnane-3,11,20-

ene-3,11,20-trione. This compound as well as the lower 1la-alkoxy-l1,19-epoxypregn-4-ene-3,20-diones, produced therefrom by hydrogenation with palladium followed by acidic treatment in the corresponding alkanol, inhibit the sodium retention produced by aldosterone. Further hydrogenation with palladium-on-charcoal produces the 1le-alkoxy-l1,19-epoxypregnane-3,20-dione which is like wise an aldosterone inhibitor.

The compounds which constitute this invention will be further illustrated by the following examples which are presented for the purpose of illustration only and are not to be construed as limiting the invention in spirit or in scope. In these examples quantities are indicated as parts by weight.

' Example 1 A mixture of 15 parts of finely pulverized o'ualbagenin 1,19-acetonide is shaken with 600 parts of pyridine and 60 parts of acetic anhydride until solution occurs. Twelve hours later the solution is taken to dryness under vacuum and the residue is recrystallized from pyridine by addition of water.

To a solution of 11.25 parts of the 3,11-diacety-1- ouabagenin 1,19-acetonide thus obtained in 30 parts of anhydrous pyridine maintained at 15 C. is added a solution of 2.5 parts of thionyl chloride in 20 parts of pyridine in the course of 5 minutes with stirring. Agitation is continued for 10 minutes longer at l5 C. after which the mixture is diluted with chloroform, Washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered and taken to dryness under vacuum. The crystalline residue is triturated with ether and collected by filtration. Recrystallized from ethanol, the 3-11- diacetyl-14-anhyd-ro oiiabagenin 1,19-acetonide thus obtained melts at about 240-242" C. Infrared maxima are observed at 2.84, 3.42, 5.72, 6:13, 8.09,-9.06, 9.82, 10.94. and 12.78 microns. The rotation of the chloroform solution or is 4.0.

By substituting in the foregoing example, 70 parts of propionic anhydride for the acetic anhydride there is obtained 3,1l-dipropionyl-14-anhydroouabagenin 1,19 acetonide.

Example 2 A mixture of 5.44 parts of 3,11-diacetyl-14-anhydroouabagenin 1,19-acetonide, 1.5 parts of 5% palladiumon-charcoal catalyst, and 50 parts of anhydrous acetic acid is shaken in an atmosphere of hydrogen until 1 equivalent is absorbed. The mixture is then filtered and the filtrate is evaporated to dryness under vacuum at C. When the residue is triturated with acetone and other a colorless crystalline product is obtained. The crystals are collected on a filter, Washed with ether and dried. On recrystallization from acetone and petroleum ether there is obtained 3,1l-diacetyl-l4-desoxyouabagenin 1,19

acetonide melting at about 260-263 C. Infrared maxima are observed at 2.82, 3.39, 5.72, 6.13, 8.09, 9.52, and;

10.38 microns. The rotation of the chloroform solution ca is +227". The compound has the structural formula 0 CHsCOP H ogre/CH3 5 CH3 K o :A

on ooo Y 3 '3 a Substitution of 5.6 parts of 3,1l-dipropionyl-14-anhydroouabagenin 1,19-acetonide as the starting material yields 3,11-dipropionyl-4-desoxyouabagenin 1,19-acetonide.

Example 3 A solution of 6 parts of 3,1l-diacetyh14-desoxyouabagenin 1,19-acetonide in 100 parts of ethyl acetate and 100 parts of dichloromethane is saturated with ozone at -80 for 1 hour. The solution is then stirred with 6 parts of zinc and 18 parts of acetic acid for 15 minutes. The mixture is diluted with dichloromethane and filtered. The filtrate is washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered and taken to dryness under vacuum. The residue is dissolvedin 50% aqueous methanol containing 1.05 parts of potassium bicarbonate. This mixture is permitted to stand for 18 hours after which it is concentrated to a small volume at 30 C. and extracted with chloroform. The extract is dried over sodium sulfate and taken to dryness under vacuum. The residue, when triturated With acetone and ether, yields a crystalline product which on recrystallization from acetone forms 35,1lot-diacetoxy-lB,5,8,19,21-tetrahydroxypregnan-ZO-one 1,19-acetonide melting at about 24l-243 C. Infrared maxima are observed at 2.90, 2.98, 5.77, 8.09, 10.40, 10.95, and 12.50 microns. The rotation of the chloroform solution 04 is +57.6. The compound has the structural formula O (I) l/\ I CE: I

CHr-COO-V Example 4 A mixture of 4.65 parts of 313,11a-diacetoxy-1fi,5fi,19, 2l-tetrahydroxypregnan-ZO-one 1,19-acetonide, 2.75 parts of p-toluenesulfonyl chloride, and 50 parts of anhydrous pyridine is permitted to stand at C. for 16 hours. To the mixture are added 40 parts of ice and 500 parts of water. The colorless crystalline precipitate which separates is collected on a filter, washed with water and ether, and dried. The 35,1la-diacetoxy-2l-(p-toluenesulfonoxy) 15,56, 1 9-trihydroxypregnan-ZO-one 1,19-acetonide melts at about 205208 C. with decomposition. Infrared maxima are observed at 2.83, 3.40, 5.78, 6.28, 8.02, 8.50, 10.08, 12.18 and 12.48 microns. The specific rotation of a chloroform solution u is +606". A solution of 1 part of this product, 0.3 part of sodium iodide and 20 parts of acetone is refluxed minutes and then evaporated to dryness. The residue is extracted With chloroform and the chloroform extract is filtered and evaporated to dryness. The residue, containing 3,8,11a-diacetoxy-2l-iodo- 13,55,19 trihydroxypregnan 20 one 1,19 acetonide, is stirred with 1 part of zinc and 3 parts of acetic acid for 5 minutes. The mixture is diluted with chloroform and filtered. The filtrate is. washed with aqueous sodium bicarbonate, dried over sodium sulfate, and evaporated to dryness. The crude crystalline residue is recrystallized from acetone and petroleum ether to give 3l9,llm-diacetoxy 15,55,19 trihydroxypregnan 20 one 1,19- acetonide melting at about 229-230" C. Infrared maxima are observed at 2.82, 3.38, 5 .76, 5.88, 7.22, 8.09, 11.55, and 12.50 microns. The rotation of the chloroform solution can is +649.

Substituting as the starting material 3B,l1a-dipropion oxy-lfl,5fl,19,21-tetrahydroxypregnan-ZO-one 1,19-acetonide there is obtained 35,1la-dipropionoxy-lflfifl,19-trihydroxypregnan-ZO-one 1,19-acetonide. The infrared absorption spectrum shows maxima at 2.83, 3.39, 5.77, 5.87 and 8.08 microns. The compound has the structural formula CIHsCO? CH5 CH: OH: I

Example 5 A mixture of 3 parts of 313,11a-diacetoxy-1fi,5fi,19-trihydroxypregnan-ZO-one 1,,19-acetonide, 12 parts of sodium carbonate, 50 parts of water and parts of methanol is refluxed for 4 hours in an atmosphere of nitrogen. The mixture is then distilled under vacuum until the methanol has been removed. The resulting aqueous solution is thoroughly extracted with chloroform. The chloroform extract is dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue is dissolved in pyridine and stirred for 18 hours with a mixture of 3 parts of chromic anhydride and 40 parts of pyridine. Then the mixture is diluted with 200 parts of chloroform and filtered. The filtrate is washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered and evaporated to dryness under vacuum. The residue is dissolved in 100 parts of ethanol and the solution is stirred at reflux for 1 hour with 29 parts of basic alumina. The mixture is filtered and the alumina is twice extracted with 100 part portions of ethanol. The ethanolic extracts are combined and taken to dryness under vacuum. The residue is dried under vacuum to yield 5,8,19-dihydroxypregn-1-ene-3,l1,20-trione. A methanolic solution shows an ultraviolet maximum at about 227 millimicrons with a molecular extinction coefiicient of about 11,000. A chloroform solution shows infrared maxima at about 2.72, 2.90, 3.37, 5.83 and 5.93 microns.

Example 6 A mixture of 4 parts of 513,19-dihydroxypregn-l-ene- 3,11,20-trione, 100 parts of methanol and 0.4 part of a 5% palladiumon-charcoal catalyst is stirred in an at mosphere of hydrogen until absorption ceases. The resulting mixture is filtered and 0.4 part of p-toluenesulfonic acid are added to the filtrate. The solution is permitted to stand for 12 hours and then concentrated to a small volume and cooled. The precipitate is collected on a filter washed with a small amount of methanol and dried to yield 1la-methoxy-l1,19-epoxypregn-4-ene-3,20-dione. A methanolic solution shows an ultraviolet maximum at about 240 millimicrons with an extinction coefiicient of about 15,000. Substitution of 100 parts of ethanol in the foregoing procedure yields 11a-ethoxy-11,19-epoxypregn-4-ene-3,20-dione, which shows ultraviolet maximum at about 240 millimicrons with a molecular extinction Irv 5 coeflicient of about 15,600. It has the structural formula QCRHB 0 i l HQC Example 7 A mixture of 2 parts of l lcz-methoxy-l1,19-epoxypregn-4-ene-3,20-dione, 50 parts of methanol and 0.2 part of 5% palladium-on-charcoal catalyst is stirred in an atmosphere of hydrogen until absorption ceases. The mixture is filtered and the filtrate is concentrated to a small volume and cooled. The product which crystallizes is collected on a filter, washed with methanol and dried. There is thus obtained 11a-methoxy-11,19-epoxypregnane-3,11,20-trione melting at about 147-148 C.

2. 3,6,11a-diactyl-14-desoxyoubagenin, 1,19-acetonideQ 3. A compound of the structural formula CH3 CH3 ll CHzX i 1/\ OH: I 15 R400 3 wherein R is a lower alkyl radical and X is a member of the class consisting of hydrogen, iodine and hydroxy radicals.

0 4. 3,9,11wdiacctoxy-1p,55,19,21-tetrahydroxypregnan- -one 1,19-acetonide.

5. 35,11u-diacetoxy-1fl,5fl,19-trihydroxypregnan-20-one, 1,19-acetonide.

No references cited.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION atent No. 2,976.284 March 21, 1961 "John 's l 'Baran It is hereby certified that errior appears in the above numbered patent requiring correction and that the said Letters Patent. should read as corrected below Column 3, line 3, for "-dipropionyl-le" read -dipropionyll4- lines'47'and 48, for "-one 19 acetonide" read one l,l9-acetonide column 6, line 3, for "3[3,ll -diactyl-" read 3B', 1-l -diacetyl (SEAL) Attest:

ERNEST W. SWIDER Attesting Officer DAVID'L. LADD Commissioner of Patents USCOMM-DC- 

3. A COMPOUND OF THE STRUCTURAL FORMULA 